There are more than 400,000 sudden cardiac deaths annually in the U.S, of which 85% or more are caused by ventricular tachyarrhythmias. Medications are an important modifiable risk factor because many have effects that can provoke lethal arrhythmias. There is increasing suspicion that several drugs in 4 widely used classes of non-cardiovascular medications-fluoroquinolone and macrolide antibiotics, antipsychotics, and antidepressants- are pro-arrhythmic and thus increase the risk of sudden cardiac death. We have published epidemiologic studies that quantified the risk conferred by older antipsychotics and antidepressants as well as oral erythromycin. The current project will extend these studies to newer medications that are used by an estimated 20% of adults in the U.S. Studies of surrogate markers suggest that the pro-arrhythmic effects of these drugs vary markedly. Specific aim 1 tests the hypothesis that there is corresponding variation in risk of sudden cardiac death. In vivo data suggest that concurrent use of study drugs with other common medications that inhibit their metabolism could markedly increase drug concentrations, and thus risk of arrhythmias. Specific aim 2 tests the hypothesis that these pharmacokinetic interactions, defined a priori, increase risk of sudden cardiac death. The hypokalemia caused by the commonly used potassium-wasting diuretics may amplify the pro-arrhythmic effects of medications. Specific aim 3 tests the hypothesis that concurrent use of study drugs and these diuretics increases risk of sudden cardiac death. We will conduct a retrospective cohort study in TennCare, Tennessee's expanded Medicaid program. Computerized TennCare files, linked with death certificates, provide the information necessary to define the cohort, classify followup according to medication exposure and potential confounders, and identify cases of sudden cardiac death using a validated computer case definition we have developed. The cohort will include an estimated 800,000 persons with 15,000 sudden cardiac deaths during 5,000,000 person years of followup and thus will have excellent power for risk estimates. The study will provide data that clinicians need to prescribe these widely used medications in a way that minimizes the risk of sudden cardiac death.